| First Author | Affortit C | Year | 2022 |
| Journal | Sci Signal | Volume | 15 |
| Issue | 738 | Pages | eabj4583 |
| PubMed ID | 35700264 | Mgi Jnum | J:360689 |
| Mgi Id | MGI:7850891 | Doi | 10.1126/scisignal.abj4583 |
| Citation | Affortit C, et al. (2022) A disease-associated mutation in thyroid hormone receptor alpha1 causes hearing loss and sensory hair cell patterning defects in mice. Sci Signal 15(738):eabj4583 |
| abstractText | Resistance to thyroid hormone due to mutations in THRA, which encodes the thyroid hormone receptor alpha (TRalpha1), shows variable clinical presentation. Mutations affecting TRbeta1 and TRbeta2 cause deafness in mice and have been associated with deafness in humans. To test whether TRalpha1 also affects hearing function, we used mice heterozygous for a frameshift mutation in Thra that is similar to human THRA mutations (Thra(S1/+) mice) and reduces tissue sensitivity to thyroid hormone. Compared to wild-type littermates, Thra(S1/+) mice showed moderate high-frequency sensorineural hearing loss as juveniles and increased age-related hearing loss. Ultrastructural examination revealed aberrant orientation of ~20% of sensory outer hair cells (OHCs), as well as increased numbers of mitochondria with fragmented morphology and autophagic vacuoles in both OHCs and auditory nerve fibers. Molecular dissection of the OHC lateral wall components revealed that the potassium ion channel Kcnq4 was aberrantly targeted to the cytoplasm of mutant OHCs. In addition, mutant cochleae showed increased oxidative stress, autophagy, and mitophagy associated with greater age-related cochlear cell damage, demonstrating that TRalpha1 is required for proper development of OHCs and for maintenance of OHC function. These findings suggest that patients with THRA mutations may present underdiagnosed, mild hearing loss and may be more susceptible to age-related hearing loss. |
